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Chlorpromazine

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GENERAL FEATURES

Name: Chlorpromazine
Generic Names:10H-Phenothiazine-10-propanamine, 2-chloro-N,N-dimethyl-; Phenothiazine, 2-chloro-10-[3-(dimethylamino)propyl]-;2-Chloro-10-[3-(Dimethylamino)propyl]phenothiazine; 2-Chloropromazine; Chloropromazine; Chlorpromazin; 2-Cloro-10 (3-dimetilaminopropil)fenotiazina; Clorpromazina; [1]
Trade Names:Aminazin; Aminazine; Ampliactil; Amplictil; Chlor-Promanyl; Chlorderazin; Chlorpromados; Contomin; CPZ; Elmarin; Esmind; Fenactil; Fenaktyl; Fraction AB; HL 5746; Largactil; Largactilothiazine; Largactyl; Megaphen; Novomazina; Phenactyl; Plegomasine; Proma; Promactil; Promazil; Propaphenin; Prozil; Sanopron; SKF 2601-A; Thorazine; Torazina; Wintermin; 4560 R.P.; Aminasine; Amplicitil; Psychozine; 2601-A; RP-4560; BC 135 [1]
IUPAC name: 3-[2-chlorophenothiazin-10-yl]-N,N-dimethylpropan-1-amine [1]
Molecular Formula: C17H19CIN2S[2]
Molecular Weight: 318.864 [g/mol][1]
Structure: Adopted from  [56]
Functional Group/chemical constitution:: CPZ has the phenothiazine nucleus, which consists of two benzene rings joined by sulphur and a nitrogen atom Comes under aliphatic group of Phenothiazines. A dimethylaminopropyl side chain is found in CPZ at position R1. [3]
Chemical Nature: It decomposes to yellow, pink and finally violet colour on exposure to air, water insoluble[2] Cationic amphiphilic drug[4], acts as cationic detergent[5] It has been shown in a study that chlorpromazine forms micelles at concentrations higher than 5. 10[-5] M in chlorpromazine in the absence of lipids and the formation of mixed micelles in the presence of lipids[6] Chlorpromazine behaves differently to ultraviolet energy under aerobic and anaerobic conditions. Under the aerobic condition oxidation products prevail, and the sulfoxide and N-oxide are formed; however, under the anaerobic condition, the polymerization process predominates and the polymer was found to be the major product [7]. Upon irradiation chlorpromazine yields a variety of free radicals including the corresponding cation radical[via photoionization],the neutral promazinyl radical and a chlorine atom[Cl.][via homolytic cleavage], and a sulfur-centered peroxy radical[8].When a CPZ solution undergoes mild oxidation it becomes reddish in color (with an absorption band at 530-540 mmicro)[9]
Actions & Indications: Pharmcological Action-
Antiemetic,
Dopamine inhibitor,
Antipsychotic Agent,
Alpha-adrenergic blocking agent,
Weak antimuscarinic agent,
Antipruritic & antiserotonin agent,
Weak antihistaminic agent & ganglio-blocking agent[2]
Known to have vasoconstrictive effects [5]
; however it is also reported to be used as effective systemic vasodilator [10][11]
Membrane-active drug[2]
A study reports that CPZ [1.2 mg intra-arterial, 50 mg intravenous] increases the peripheral blood flow in man [12].
A study with cats provided an evidence that chlorpromazine possesses an anti-adrenaline action but very little anti-noradrenaline action[13].
Weak Anti-acetylcholine and weak antihistaminic of CPZ was seen in guinea pigs [14].
Therapeutic benefits/Indications–
Chlorpromazine(Thorazine) is used to treat the intractable hiccups in patients[15]
Chlorpromazine is a useful treatment for this group of patients, especially when aggressiveness, overactivity , or psychotic tension is a prominent symptom[16] Chlorpromazine is used to alleviate the pain and nervous manifestations of porphyria[17]
It is emerging as an adjuvant chemotherapeutic agent for the treatment of neoplasia[18]
Chlorpromazine is useful for relief of restlessness and agitation-for example, in patients with painful inoperable carcinoma, especially if complicated by persistent vomiting or for restlessness and agitation in other physical disorders or associated with old age. In acute and chronic schizophrenia, for relieving anxiety, tension, agitation and disturbed behaviour in other psychiatric illnesses, in management of patients with senile dementia and also for the management of disturbed overactive behaviour in children and in mental defects of all ages [3].
Chlorpromazine effectively counteracts systemic vasoconstriction induced by cardiopulmonary bypass without serious side effects in neonatal cardiac surgery [10].
A small number of patients with evidence of severe cerebral vascular disease were clinically improved by chlorpromazine [19].
Chlorpromazine has proved to be an efficient means of treating chronic prolonged pain due to cancer particularly in those with addiction to large doses of narcotics. This is accomplished by substituting small doses of the narcotic together with chlorpromazine, and given at wide intervals [three or four times in 24 hours][19].
Other therapeutic properties/Potential therapeutic benefits-
Human study-
Echinocytic shape transformation and subsequent vesiculation of RBCs which commonly occur during ATP depletion were inhibited by chlorpromazine[20]
Chlorpromazine can inhibit a Ca2+ -mediated cell death[21] at favorable concentrations [10[-6]-10[-5] M], it caused a drastic decrease in cell viability at higher concentrations [10[-4]-10[-3] M] in a human neuroblastoma cell line thus chlorpromazine has biphasic effects on cell viability according to the concentrations added, i.e. a protective effect against cell damage caused by Ca2+, and a direct toxic effect independent of extracellular Ca2+ or of lipid peroxidation.[22]
It exerts cytotoxic effect on normal and neoplastic cells[18]
30microM of CPZ brought about the complete growth inhibition of hypernephroma cell in vitro[23]
In human volunteers, CPZ does not inhibit the production of TNF-α, IL-1 β, and IL-1ra and also does not up-regulate the production of IL-10[24]
Symptoms of delirium in medically hospitalized AIDS patients may be treated efficaciously with few side effects by using low-dose CPZ[25]
CPZ [0.2mM] antineoplasia is seen in mammalian cell cultures [Human P3 teratocarcinoma] when exposed to monochromatic UVA radiation at 334 nm by enhancing the yield of DNA single strand breaks. The study also suggested that CPZ may exert antineoplastic effect against UV-induced skin tumors by the induction of DNA damage[26]
CPZ protected human leukocytes from osmotic haemolysis, increased the mean cellular volume of RBC in isotonic medium, decreased the sedimentation rate of erythrocytes [27].
Chlorpromazine, at concentrations above 5 × 10-6 M caused a dose dependent inhibition of hypotonic hemolysis, also it decreased cardiac excitability, contractility and potassium efflux[28].
The drug induced increase of the critical volume of the erythrocytes[29].
CPZ inhibited [5-hydroxytryptamine] 5-HT-induced platelet aggregation [30] and at low concentration, CPZ inhibits ADP-induced second stage of platelet aggregation in vitro [31].
Animal study-
In mice, CPZ is found to be inhibiting LPS-induced toxicity[ (LPS)-induced hypoferramia and lethality reduced by CPZ-4mg/kg[32] and TNF production by up-regulating the production of IL-10[33]
It has been shown that chlorpromazine [4mg/kg] has a protective effect against TNF in adrenoectomized mice and mice pretreated with actinomycin D [CPZ [4mg/kg]; while it failed to protect mice against TNF in vivo [34]. It is mentioned in a study that CPZ[4mg/kg] protects against IL-1 activity in vivo[35].
CPZ [1-15microM] inhibited lactoferrin release by PMN in vitro. CPZ [25microM] inhibited Phorbol myristate acetate [PMA]-stimulated O2- generation and its release as well as chemotaxis of PMN. CPZ is a modulator of Polymorphonuclear neutrophils [PMN] function in vitro and in vivo[32].
The drug was also observed to have additive effects on hyperthermic killing of L5178Y cells[36].
CPZ-induced cytotoxicity is mediated through autophagic cell death in PTEN[Phosphatase and tensin homolog deleted on chromosome 10]-null U-87MG glioma cells by inhibiting PI3K/AKT/mTOR pathway[37].
CPZ significantly inhibited solar UV-induced squamous cell carcinoma in hairless mice[26].
CPZ[70microM] protects rat brain tissue from hypoxia-induced irreversible loss of synaptic transmission by delaying occurrence of spreading-depression[SD][38].
The neuroprotective action of CPZ is dose-dependent in the ischemic spinal cord of rabbits. The lower protective dose is found to be 1 mg/kg[39].
The protection of renal function against ischemia/reperfusion injury is promoted by CPZ at a dosage of 3mg/kg in a rat model[40].
Hypothermia or possibly CPZ considerably modulates drug toxicity and possible anti-tumor activity[41]CPZ showed antitumor activity in sarcoma 37 grown in CAF1 mice[42] and also in many other tumors [43, 44, 45, 46, 37, 36]
In a study with dogs, chlorpromazine [2 mg/ kg] was found to be effective both for facilitating the production of hypothermia and preventing shivering and also shown to have the ability of vasodilation [48].
It is showed in study with cats showed that chlorpromazine has a depressant effect on skeletal muscles [13].
The incidence of convulsions due to insulin in mice was reduced by chlorpromazine. It produced reduced a hypoglycaemia due to insulin in rabbits [14].
A study with viruses proposed that CPZ could be employed in preparation of inactivated viral vaccines or in photochemotherapy of accessible viral dermatoses[49].
CPZ [1, 5, 10, 20, 40microM] inhibited proliferation of C6 rat glioma cells. The inhibitory effect found was concentration and time-dependent [50].
Chlorpromazine (CPZ) is an effective cyanide antidote with its greatest efficacy displayed when combined with the other antidotes, sodium nitrite and sodium thiosulfate[51].
Chlorpromazine hydrochloride was found to exhibit a broad spectrum of antibacterial activity with an MIC between 8 and 15 microg/ml in minimal salts media[52]. In a study, CPZ is suggested to be suitable candidate for the treatment of Creutzfeldt–Jakob disease and other prion diseases[53] also CPZ found to attenuate β[25-35], an active sequence of Amyloid β protein[Aβ] in primary cultures of rat cortical neurons and PC12 cells[54] whereas in another study CPZ was found to be ineffective in treating patients with Creutzfeldt–Jakob disease[55].
REFERNCES
1. NIST chemistry webbook
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